Abstract/Project Summary Fatigue is one of the most distressing and commonly reported side effects of chemo-radiation (CRT), with up to 78% of rectal cancer patients complaining of severe fatigue during CRT. While the etiology and associated mechanism of the cancer-related fatigue during CRT treatment remain elusive, it has been suggested that dysbiosis (an imbalance in the intestinal microbiota in the gut) may contribute to worsening of fatigue during a patients? pelvic CRT. This study will contribute to address the knowledge gap in symptom research and the health literature by providing initial evidence of the biologic/gut microbial processes related to the relationship among CRT, dysbiosis, and fatigue in the rectal cancer population, so that more innovative and individualized interventions can be developed. The proposed research is guided by a model of chemotherapy-related side effects. The training plan was designed to allow the applicant to expand her theoretical knowledge and skills in symptom phenotyping and conducting bio-behavioral and microbiome research in order to meet the NRSA traineeship goals and launch a career as an independent nurse scientists. An experienced team of scientists will lead the research training plan as related to the following objectives: (1) to enhance her understanding of the science related to the proposed mechanism linking CRT-induced gut microbiome dysbiosis and fatigue; (2) to increase her understanding of the characterization of CRT-related fatigue phenotypes with patient biological and clinical data, and microbiome data collection techniques and analysis through a bedside-to-bench approach; (3) to obtain comprehensive training and knowledge in microbiome research including stool collection and processing, bacterial 16S rRNA amplicon sequencing, shotgun metagenomics analysis and interpretation of microbiome-derived metagenomics data; and (4) to improve scientific writing skills and building collaborations with experts in the field of bio-behavioral/symptom management/microbiome research to successfully publish in high-impact, peer-reviewed journals, and submit competitive grant applications. The training plan is for twenty four months and includes six core areas: didactic; interdisciplinary seminars; mentorship; laboratory training; research; and dissemination. The specific aims of the proposed study are to: Aim 1: Examine the temporal changes in diversity of the gut microbiome over the course of CRT of adults with localized rectal cancers. Aim 1a: To investigate whether the intensity of fatigue during CRT is associated with the gut microbial diversity changes during the course of treatment. Aim 2: Examine the temporal changes on the abundances of specific gut microbes of adults with localized rectal cancers over the course of CRT. Aim 2a: To investigate the associations between changes in the gut microbial abundance with changes in fatigue scores during the course of CRT. By focusing on the innovative investigation of the relationship between gut microbial changes and fatigue symptoms during CRT, this study aligns with the mission of NINR calling for studies on patient-centered bio-behavioral research that promote health and enhanced quality of life.